SMAD4 Suppresses Colitis-associated Carcinoma Through Inhibition of CCL20/CCR6-mediated Inflammation

Hanna, David N; Smith, Paula Marincola; Novitskiy, Sergey V.; Washington, M. Kay; Zi, Jinghuan; Weaver, Connie; Hamaamen, Jalal A.; Lewis, Keeli B.; Zhu, Jing; Yang, Jing; Liu, Qi; Beauchamp, R. Daniel; Means, Anna L.

doi:10.1053/j.gastro.2022.07.016

Cited by 22 publications

(17 citation statements)

References 49 publications

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“…The transcriptome of peripheral blood monocytes exposed to acute heat exposure had an inflammatory signature consisting of chemokines (C‐C motif ligand, C‐X‐C motif ligand, interleukin), complement C1qA chain, IFN‐γ, TNF, NLRP3, and colony‐stimulating factor 3. Accumulating evidence indicates that multiple inflammatory cytokines such as TNF‐α, IFN‐γ, CCL20, IL1, and IL6 induce inflammation (Dinarello, 2011; Hanna et al., 2022; Jones & Jenkins, 2018; Karki et al., 2021). C1qA, the initiating molecule of the classical complement cascade, can trigger inflammation, and blocking C1q function reduces chronic glial inflammation and neuron loss (Holden et al., 2021).…”

Section: Discussionmentioning

confidence: 99%

Time‐series transcriptome reveals inflammatory signature in monocytes and neutrophils following acute heat exposure in mine rescuers

Wen,

Wang,

Cheng

et al. 2024

Physiological Reports

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Occupational exposure to extreme high temperatures and the increasing global temperatures necessitates a deeper understanding of the impact of heat exposure on human health. However, the molecular mechanisms underlying the response of monocytes and neutrophils to heat exposure in occupational population remain to be fully elucidated. This study used longitudinal transcriptome to assess the impact of acute heat exposure (50°C for 30 min) in 10 subjects from a mine rescue team before acute heat exposure (baseline) and at 5 min, 30 min, 1 h, and 24 h after acute heat exposure (recovery). The time‐series analysis revealed a coordinated molecular choreography of changes involving inflammation, coagulation, extracellular matrix, and energy metabolism. Importantly, the study characterized the inflammatory signature associated with heat exposure in monocytes and neutrophils, as evidenced by the rapid activation of the inflammation‐related transcriptome following heat exposure. Additionally, we pinpointed potential regulators, such as NR4A1, FOSL1, EGR3, and ATF3. In summary, the study suggested that the initial response to heat stress in monocytes and neutrophils from mine rescue team member was primarily characterized by a pro‐inflammatory stress response, which could potentially lead to the development of inflammation and ultimately result in a systemic inflammatory response in heatstroke.

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Section: Discussionmentioning

confidence: 99%

Time‐series transcriptome reveals inflammatory signature in monocytes and neutrophils following acute heat exposure in mine rescuers

Wen,

Wang,

Cheng

et al. 2024

Physiological Reports

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“…Previous studies used haploinsufficiency 71 , or partial deletion 23 , of Smad4 loss in the epithelium and show that Smad4 loss promotes colitis and colitis-associated cancer 23, 24 . Furthermore, in contrast to previous studies that used DSS-IBD mouse models of chronic inflammation, our study employed a model of acute inflammation 23,24,70 . However, given the role of Smad4 in genomic stability 21, 22, 72 and tumor suppression 16, 17 , it is not surprising that Smad4 loss led to tumorigenesis in the chronic inflammatory DSS-IBD mouse model, especially in the presence of a DNA-damaging agent such as AOM.…”

Section: Discussionmentioning

confidence: 99%

Smad4 Loss in the Mouse Intestinal Epithelium Alleviates the Pathological Fibrotic Response to Injury in the Colon

Hashemi,

Hui,

et al. 2024

Preprint

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Mucosal healing is associated with better clinical outcomes in patients with inflammatory bowel diseases (IBDs). Unresolved injury and inflammation, on the other hand, increases pathological fibrosis and the predisposition to cancer. Loss of Smad4, a tumor suppressor, is known to increase colitis-associated cancer in mouse models of chronic IBD. Since common biological processes are involved in both injury repair and tumor growth, we sought to investigate the effect of Smad4 loss on the response to epithelial injury. To this end, Smad4 was knocked out specifically in the intestinal epithelium and transcriptomic and morphological changes compared between wild type mice and Smad4 knock out mice after DSS-induced injury. We find that Smad4 loss alleviates pathological fibrosis and enhances mucosal repair. The transcriptomic changes specific to epithelium indicate molecular changes that affect epithelial extracellular matrix (ECM) and promote enhanced mucosal repair. These findings suggest that the biological processes that promote wound healing alleviate the pathological fibrotic response to DSS. Therefore, these mucosal repair processes could be exploited to develop therapies that promote normal wound healing and prevent fibrosis.NEW AND NOTEWORTHYWe show that transcriptomic changes due to Smad4 loss in the colonic epithelium alleviates the pathological fibrotic response to DSS in an IBD mouse model of acute inflammation. Most notably, we find that collagen deposition in the epithelial ECM, as opposed to that in the lamina propria, correlates with epithelial changes that enhance wound healing. This is the first report on a mouse model providing alleviated fibrotic response in a DSS-IBD mouse modelin vivo.

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“…Smad4, a central signalling component of transforming growth factor β (TGF‐β), is a multifunctional cytokine that regulates cell growth and differentiation 15–17 . Smad4 was regarded as an important tumour suppressor in various types of cancers 18–21 . The role of Smad4 as a tumour suppressor was initially identified in pancreatic cancer as being absent in pancreatic cancer 4 (DPC4)4, 22–24 and since then loss of Smad4 has been identified in a key driver in skin cancer, 25 head and neck cancer, 26 and other cancers 16,19 .…”

Section: Introductionmentioning

confidence: 99%

“…[18][19][20][21] The role of Smad4 as a tumour suppressor was initially identified in pancreatic cancer as being absent in pancreatic cancer 4 (DPC4)4, [22][23][24] and since then loss of Smad4 has been identified in a key driver in skin cancer, 25 head and neck cancer, 26 and other cancers. 16,19 Epithelial deficiency of Smad4 could lead to overexpression of TGFβ which then was released into the tumour microenvironment to promote squamous carcinoma progression through pro-inflammatory and immune evasion mechanisms. 19,27,28 However, mechanisms governing dysregulation of Smad4 in OSCC was unclear.…”

mentioning

confidence: 99%

“…16,19 Epithelial deficiency of Smad4 could lead to overexpression of TGFβ which then was released into the tumour microenvironment to promote squamous carcinoma progression through pro-inflammatory and immune evasion mechanisms. 19,27,28 However, mechanisms governing dysregulation of Smad4 in OSCC was unclear. It should be further investigated to gain insight into prognosis and therapeutic approaches to potentially guide future clinical trials and improve the prognosis of patients with OSCC.…”

mentioning

confidence: 99%

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CircLDLRAD3 inhibits Oral squamous cell carcinoma progression by regulating miR‐558/Smad4/TGF‐β

Zhang

Guo

Liu

et al. 2023

J Cellular Molecular Medi

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Oral squamous cell carcinoma (OSCC) is a malignant neoplasm with high mortality and morbidity. The role of circRNA and its molecular mechanism in OSCC remains largely unknown. The study aims to explore the role of a novel circular RNA (circLDLRAD3) in OSCC and its underlying mechanism. PCR and fluorescence in situ hybridization were used to explore the expression features of circLDLRAD3 in OSCC. The effects of circLDLRAD3 on the behaviour of OSCC were investigated using CCK‐8, colony formation assay, transwell and animal experiments. Bioinformatics analysis along with dual luciferase reporter assay and RIP assay were used to reveal the interaction between circLDLRAD3, miR‐558 and Smad4. It was revealed that circLDLRAD3 exhibited low expression status in OSCC. CircLDLRAD3 inhibits proliferation, migration, and invasion of OSCC cells both in vitro and in vivo. Mechanistically, circLDLRAD3 could bind with miR‐558 to positively regulate its target gene Smad4 expression. Rescue experiments further confirmed both miR‐558 overexpression and Smad4 knockdown could reverse the influence of circLDLRAD3 on OSCC phenotypes. Moreover, circLDLRAD3 regulate the TGF‐β signalling pathways to influence EMT through miR‐558/Smad4 axis. Our study found that circLDLRAD3 is downregulated in OSCC and verified its tumour suppressor function and mechanism in OSCC through sponging miR‐558 to regulate miR‐558/Smad4/TGF‐β axis. The characterization of such regulating network uncovers an important mechanism underlying OSCC progression, which could provide promising targets targeted therapy strategies for OSCC in the future.

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SMAD4 Suppresses Colitis-associated Carcinoma Through Inhibition of CCL20/CCR6-mediated Inflammation

Cited by 22 publications

References 49 publications

Time‐series transcriptome reveals inflammatory signature in monocytes and neutrophils following acute heat exposure in mine rescuers

Time‐series transcriptome reveals inflammatory signature in monocytes and neutrophils following acute heat exposure in mine rescuers

Smad4 Loss in the Mouse Intestinal Epithelium Alleviates the Pathological Fibrotic Response to Injury in the Colon

CircLDLRAD3 inhibits Oral squamous cell carcinoma progression by regulating miR‐558/Smad4/TGF‐β

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